Skip to main content
SpringerLink
Log in

ICU Management: Disseminated Intravascular Coagulation (DIC)

  • Chapter
  • First Online:
Textbook of Polytrauma Management

  • 1614 Accesses

Abstract

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic inflammation, activation of coagulation, insufficient anticoagulation control, increased followed by inhibition of fibrinolysis, and endothelial injury. Damage-associated molecular patterns (DAMPs), such as histones, and neutrophil extracellular traps, comprising neutrophil DAMPs and neutrophil elastase, induce all changes observed in DIC and thus, play pivotal roles in the pathogenesis of DIC. In DIC, platelet dysfunction and consumption coagulopathy induce oozing-type bleeding, enhancing surgical bleeding. A decreased oxygen delivery to cells and tissues due to microvascular thrombosis associated with endothelial injury and direct cellular injury by histones induces multiple organ dysfunction syndrome (MODS). Trauma has been a leading cause of DIC for over 50 years. DIC influences the outcome of trauma patients in two ways: a fibrinolytic phenotype immediately after injury exacerbates bleeding via increased fibrin(ogen)olysis, which progresses to a thrombotic phenotype giving rise to MODS in the late stage. Many studies have shown an increased transfusion requirement and higher rates of MODS and mortality in DIC than in non-DIC. To improve outcomes, DIC and trauma should be simultaneously treated, targeting patients with definitively diagnosed DIC and a high disease severity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016;2:16037. https://doi.org/10.1038/nrdp.2016.37.

    Article  PubMed  Google Scholar 

  2. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–74.

    Google Scholar 

  3. Nasraway SA Jr. Sepsis research: we must change course. Crit Care Med. 1999;27:427–30. https://doi.org/10.1097/00003246-199902000-00054.

    Article  PubMed  Google Scholar 

  4. Esmon CT, Fukudome K, Mather T, Bode W, Regan LM, Stearns-Kurosawa DJ, Kurosawa S. Inflammation, sepsis, and coagulation. Haematologica. 1999;84:254–9.

    CAS  PubMed  Google Scholar 

  5. Penner JA. Disseminated intravascular coagulation in patients with multiple organ failure of non-septic origin. Semin Thromb Hemost. 1998;24:45–52. https://doi.org/10.1055/s-2007-995822.

    Article  CAS  PubMed  Google Scholar 

  6. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327–30.

    Article  CAS  PubMed  Google Scholar 

  7. Gando S. Disseminated intravascular coagulation in trauma patients. Semin Thromb Hemost. 2001;27:585–92. https://doi.org/10.1055/s-2001-18864.

    Article  CAS  PubMed  Google Scholar 

  8. Keel M, Trentz O. Pathophysiology of polytrauma. Injury. 2005;36:691–709. https://doi.org/10.1016/j.injury.2004.12.037.

    Article  PubMed  Google Scholar 

  9. Gando S. Tissue factor in trauma and organ dysfunction. Semin Thromb Hemost. 2006;32:48–53. https://doi.org/10.1055/s-2006-933340.

    Article  CAS  PubMed  Google Scholar 

  10. Squizzato A, Gallo A, Levi M, Iba T, Levy JH, Erez O, Ten Cate H, Solh Z, Gando S, Vicente V, Di Nisio M. Underlying disorders of disseminated intravascular coagulation: Communication from the ISTH SSC Subcommittees on Disseminated Intravascular Coagulation and Perioperative and Critical Care Thrombosis and Hemostasis. J Thromb Haemost. 2020;18:2400–7. https://doi.org/10.1111/jth.14946.

    Article  PubMed  Google Scholar 

  11. Toh CH, Dennis M. Disseminated intravascular coagulation: old disease, new hope. BMJ. 2003;327:974–7. https://doi.org/10.1136/bmj.327.7421.974.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Moore HB, Gando S, Iba T, Kim PY, Yeh CH, Brohi K, Hunt BJ, Levy JH, Draxler DF, Stanworth S, Görlinger K, Neal MD, Schreiber MA, Barrett CD, Medcalf RL, Moore EE, Mutch NJ, Thachil J, Urano T, Thomas S, Scărlătescu E, Walsh M. Defining trauma-induced coagulopathy with respect to future implications for patient management: communication from the SSC of the ISTH. J Thromb Haemost. 2020;18:740–7. https://doi.org/10.1111/jth.14690.

    Article  PubMed  Google Scholar 

  13. Gando S, Shiraishi A, Wada T, Yamakawa K, Fujishima S, Saitoh D, Kushimoto S, Ogura H, Abe T, Otomo Y. A multicenter prospective validation study on disseminated intravascular coagulation in trauma-induced coagulopathy. J Thromb Haemost. 2020;18:2232–24. https://doi.org/10.1111/jth.14931.

    Article  CAS  PubMed  Google Scholar 

  14. Gando S, Hayakawa M. Pathophysiology of trauma-induced coagulopathy and management of critical bleeding requiring massive transfusion. Semin Thromb Hemost. 2016;42:155–65. https://doi.org/10.1055/s-0035-1564831.

    Article  PubMed  Google Scholar 

  15. Hardaway RM. Disseminated intravascular coagulation syndromes. Arch Surg. 1961;83:842–50. https://doi.org/10.1001/archsurg.1961.01300180042009.

    Article  CAS  PubMed  Google Scholar 

  16. McKay DG. Trauma and disseminated intravascular coagulation. J Trauma. 1969;9:646–60. https://doi.org/10.1097/00005373-196908000-00002.

    Article  CAS  PubMed  Google Scholar 

  17. Flute PT. Coagulation and fibrinolysis after injury. J Clin Pathol Suppl (R Coll Pathol). 1970;4:102–9. https://doi.org/10.1136/jcp.s3-4.1.102.

    Article  CAS  Google Scholar 

  18. Bakhtiari K, Meijers JC, de Jonge E, Levi M. Prospective validation of the International Society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med. 2004;32:2416–21. https://doi.org/10.1097/01.ccm.0000147769.07699.e3.

    Article  PubMed  Google Scholar 

  19. Toh CH, Downey C. Performance and prognostic importance of a new clinical and laboratory scoring system for identifying non-overt disseminated intravascular coagulation. Blood Coagul Fibrinolysis. 2005;16:69–74. https://doi.org/10.1097/00001721-200501000-00011.

    Article  PubMed  Google Scholar 

  20. Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, Mayumi T, Murata A, Ikeda T, Ishikura H, Ueyama M, Ogura H, Kushimoto S, Saitoh D, Endo S, Shimazaki S. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med. 2006;34:625–31. https://doi.org/10.1097/01.ccm.0000202209.42491.38.

    Article  PubMed  Google Scholar 

  21. Gando S, Saitoh D, Ogura H, Mayumi T, Koseki K, Ikeda T, Ishikura H, Iba T, Ueyama M, Eguchi Y, Ohtomo Y, Okamoto K, Kushimoto S, Endo S, Shimazaki S. Natural history of disseminated intravascular coagulation diagnosed based on the newly established diagnostic criteria for critically ill patients: results of a multicenter, prospective survey. Crit Care Med. 2008;36:145–50. https://doi.org/10.1097/01.Ccm.0000295317.97245.2d.

    Article  PubMed  Google Scholar 

  22. Gando S, Saitoh D, Ogura H, Fujishima S, Mayumi T, Araki T, Ikeda H, Kotani J, Kushimoto S, Miki Y, Shiraishi S, Suzuki K, Suzuki Y, Takeyama N, Takuma K, Tsuruta R, Yamaguchi Y, Yamashita N, Aikawa N. A multicenter, prospective validation study of the Japanese Association for Acute Medicine disseminated intravascular coagulation scoring system in patients with severe sepsis. Crit Care. 2013;17:R111. https://doi.org/10.1186/cc12783.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, Katabami K. Application of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria for patients at an early phase of trauma. Thromb Res. 2009;124:706–10. https://doi.org/10.1016/j.thromres.2009.06.036.

    Article  CAS  PubMed  Google Scholar 

  24. Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, Katabami K. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009;124:608–13. https://doi.org/10.1016/j.thromres.2009.06.034.

    Article  CAS  PubMed  Google Scholar 

  25. Oshiro A, Yanagida Y, Gando S, Henzan N, Takahashi I, Makise H. Hemostasis during the early stages of trauma: comparison with disseminated intravascular coagulation. Crit Care. 2014;18:R61. https://doi.org/10.1186/cc13816.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Marder VJ FD, Colman RW, Levi M. Consumptive thrombohemorrhagic disorders. In: Colman RW, Marder VJ, Clowes AW, George JN, Goldhaber SZ, ed. Hemostasis and thrombosis: basic principles and clinical practice, 5th edn. Philadelphia: Lippincott Williams & Wilkins, 2006, 1571–1600.

    Google Scholar 

  27. Asakura H. Classifying types of disseminated intravascular coagulation: clinical and animal models. J Intensive Care. 2014;2:20. https://doi.org/10.1186/2052-0492-2-20.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gando S, Otomo Y. Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock. Crit Care. 2015;19:72. https://doi.org/10.1186/s13054-015-0735-x.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Menell JS, Cesarman GM, Jacovina AT, McLaughlin MA, Lev EA, Hajjar KA. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med. 1999;340:994–1004. https://doi.org/10.1056/nejm199904013401303.

    Article  CAS  PubMed  Google Scholar 

  30. Schwameis M, Schober A, Schörgenhofer C, Sperr WR, Schöchl H, Janata-Schwatczek K, Kürkciyan EI, Sterz F, Jilma B. Asphyxia by drowning induces massive bleeding due to hyperfibrinolytic disseminated intravascular coagulation. Crit Care Med. 2015;43:2394–402. https://doi.org/10.1097/ccm.0000000000001273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gando S, Wada T. Disseminated intravascular coagulation in cardiac arrest and resuscitation. J Thromb Haemost. 2019;17:1205–16. https://doi.org/10.1111/jth.14480.

    Article  PubMed  Google Scholar 

  32. Kruithof EK, Tran-Thang C, Gudinchet A, Hauert J, Nicoloso G, Genton C, Welti H, Bachmann F. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood. 1987;69:460–6.

    Article  CAS  PubMed  Google Scholar 

  33. Wada T, Gando S, Maekaw K, Katabami K, Sageshima H, Hayakawa M, Sawamura A. Disseminated intravascular coagulation with increased fibrinolysis during the early phase of isolated traumatic brain injury. Crit Care. 2017;21:219. https://doi.org/10.1186/s13054-017-1808-9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hayakawa M, Maekawa K, Kushimoto S, Kato H, Sasaki J, Ogura H, Matsuoka T, Uejima T, Morimura N, Ishikura H, Hagiwara A, Takeda M, Kaneko N, Saitoh D, Kudo D, Kanemura T, Shibusawa T, Furugori S, Nakamura Y, Shiraishi A, Murata K, Mayama G, Yaguchi A, Kim S, Takasu O, Nishiyama K. Hyperfibrinolysis in severe isolated traumatic brain injury may occur without tissue hypoperfusion: a retrospective observational multicentre study. Crit Care. 2017;21:222. https://doi.org/10.1186/s13054-017-1811-1.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gando S, Sawamura A, Hayakawa M. Trauma, shock, and disseminated intravascular coagulation: lessons from the classical literature. Ann Surg. 2011;254:10–9. https://doi.org/10.1097/SLA.0b013e31821221b1.

    Article  PubMed  Google Scholar 

  36. Gando S, Wada H, Thachil J. Differentiating disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype from coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS). J Thromb Haemost. 2013;11:826–35. https://doi.org/10.1111/jth.12190.

    Article  CAS  PubMed  Google Scholar 

  37. Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med. 2005;15:302–8. https://doi.org/10.1016/j.tcm.2005.09.005.

    Article  CAS  PubMed  Google Scholar 

  38. Gupta N, Zhao YY, Evans CE. The stimulation of thrombosis by hypoxia. Thromb Res. 2019;181:77–83. https://doi.org/10.1016/j.thromres.2019.07.013.

    Article  CAS  PubMed  Google Scholar 

  39. Hijazi N, Abu Fanne R, Abramovitch R, Yarovoi S, Higazi M, Abdeen S, Basheer M, Maraga E, Cines DB, Higazi AA. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood. 2015;125:2558–67. https://doi.org/10.1182/blood-2014-08-588442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care. 2004;1:479–88. https://doi.org/10.1385/ncc:1:4:479.

    Article  PubMed  Google Scholar 

  41. Gando S, Wada H, Kim HK, Kurosawa S, Nielsen JD, Thachil J, Toh CH. Comparison of disseminated intravascular coagulation in trauma with coagulopathy of trauma/acute coagulopathy of trauma-shock. J Thromb Haemost. 2012;10:2593–5. https://doi.org/10.1111/jth.12011.

    Article  CAS  PubMed  Google Scholar 

  42. Murakami H, Gando S, Hayakawa M, Sawamura A, Sugano M, Kubota N, Uegaki S, Jesmin S. Disseminated intravascular coagulation (DIC) at an early phase of trauma continuously proceeds to DIC at a late phase of trauma. Clin Appl Thromb Hemost. 2012;18:364–9. https://doi.org/10.1177/1076029611426138.

    Article  PubMed  Google Scholar 

  43. Esmon CT. Inflammation and thrombosis. J Thromb Haemost. 2003;1:1343–8. https://doi.org/10.1046/j.1538-7836.2003.00261.x.

    Article  CAS  PubMed  Google Scholar 

  44. Esmon CT, Xu J, Lupu F. Innate immunity and coagulation. J Thromb Haemost. 2011;9(Suppl 1):182–8. https://doi.org/10.1111/j.1538-7836.2011.04323.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gando S. Role of fibrinolysis in sepsis. Semin Thromb Hemost. 2013;39:392–9. https://doi.org/10.1055/s-0033-1334140.

    Article  CAS  PubMed  Google Scholar 

  46. Huber-Lang M, Lambris JD, Ward PA. Innate immune responses to trauma. Nat Immunol. 2018;19:327–41. https://doi.org/10.1038/s41590-018-0064-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bone RC. Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med. 1996;24:1125–8. https://doi.org/10.1097/00003246-199607000-00010.

    Article  CAS  PubMed  Google Scholar 

  48. Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol. 2013;13:34–45. https://doi.org/10.1038/nri3345.

    Article  CAS  PubMed  Google Scholar 

  49. Gando S, Nakanishi Y, Tedo I. Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome. Crit Care Med. 1995;23:1835–42. https://doi.org/10.1097/00003246-199511000-00009.

    Article  CAS  PubMed  Google Scholar 

  50. Abrams ST, Zhang N, Manson J, Liu T, Dart C, Baluwa F, Wang SS, Brohi K, Kipar A, Yu W, Wang G, Toh CH. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013;187:160–9. https://doi.org/10.1164/rccm.201206-1037OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Esmon CT. Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis. Baillieres Best Pract Res Clin Haematol. 1999;12:343–59. https://doi.org/10.1053/beha.1999.0029.

    Article  CAS  PubMed  Google Scholar 

  52. Boermeester MA, van Leeuwen PA, Coyle SM, Wolbink GJ, Hack CE, Lowry SF. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg. 1995;130:739–48. https://doi.org/10.1001/archsurg.1995.01430070061012.

    Article  CAS  PubMed  Google Scholar 

  53. van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJ, Eerenberg AJ, de Groot ER, Jansen J, Gallati H, Büller HR, et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med. 1994;179:1253–9. https://doi.org/10.1084/jem.179.4.1253.

    Article  PubMed  Google Scholar 

  54. McGill SN, Ahmed NA, Christou NV. Endothelial cells: role in infection and inflammation. World J Surg. 1998;22:171–8. https://doi.org/10.1007/s002689900366.

    Article  CAS  PubMed  Google Scholar 

  55. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998;91:3527–61.

    CAS  PubMed  Google Scholar 

  56. Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today. 1993;14:506–12. https://doi.org/10.1016/0167-5699(93)90267-o.

    Article  CAS  PubMed  Google Scholar 

  57. Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A. 1994;91:8767–71. https://doi.org/10.1073/pnas.91.19.8767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Weiss SJ. Tissue destruction by neutrophils. N Engl J Med. 1989;320:365–76. https://doi.org/10.1056/nejm198902093200606.

    Article  CAS  PubMed  Google Scholar 

  59. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454:345–59. https://doi.org/10.1007/s00424-007-0212-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Suffredini AF, Harpel PC, Parrillo JE. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med. 1989;320:1165–72. https://doi.org/10.1056/nejm198905043201802.

    Article  CAS  PubMed  Google Scholar 

  61. Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA. 1993;270:975–9.

    Article  CAS  PubMed  Google Scholar 

  62. Biemond BJ, Levi M, Ten Cate H, Van der Poll T, Büller HR, Hack CE, Ten Cate JW. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci (Lond). 1995;88:587–94. https://doi.org/10.1042/cs0880587.

    Article  CAS  Google Scholar 

  63. Gando S, Kameue T, Nanzaki S, Nakanishi Y. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost. 1996;75:224–8.

    Article  CAS  PubMed  Google Scholar 

  64. Gando S, Kameue T, Nanzaki S, Hayakawa T, Nakanishi Y. Participation of tissue factor and thrombin in posttraumatic systemic inflammatory syndrome. Crit Care Med. 1997;25:1820–6. https://doi.org/10.1097/00003246-199711000-00019.

    Article  CAS  PubMed  Google Scholar 

  65. Gando S, Tedo I, Kubota M. Posttrauma coagulation and fibrinolysis. Crit Care Med. 1992;20:594–600. https://doi.org/10.1097/00003246-199205000-00009.

    Article  CAS  PubMed  Google Scholar 

  66. Gando S, Nanzaki S, Morimoto Y, Ishitani T, Kemmotsu O. Tissue factor pathway inhibitor response does not correlate with tissue factor-induced disseminated intravascular coagulation and multiple organ dysfunction syndrome in trauma patients. Crit Care Med. 2001;29:262–6. https://doi.org/10.1097/00003246-200102000-00006.

    Article  CAS  PubMed  Google Scholar 

  67. Hayakawa M, Sawamura A, Gando S, Kubota N, Uegaki S, Shimojima H, Sugano M, Ieko M. Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase. Surgery. 2011;149:221–30. https://doi.org/10.1016/j.surg.2010.06.010.

    Article  PubMed  Google Scholar 

  68. Hayakawa M, Sawamura A, Gando S, Jesmin S, Naito S, Ieko M. A low TAFI activity and insufficient activation of fibrinolysis by both plasmin and neutrophil elastase promote organ dysfunction in disseminated intravascular coagulation associated with sepsis. Thromb Res. 2012;130:906–13. https://doi.org/10.1016/j.thromres.2012.01.015.

    Article  CAS  PubMed  Google Scholar 

  69. Gando S, Nakanishi Y, Kameue T, Nanzaki S. Soluble thrombomodulin increases in patients with disseminated intravascular coagulation and in those with multiple organ dysfunction syndrome after trauma: role of neutrophil elastase. J Trauma. 1995;39:660–4. https://doi.org/10.1097/00005373-199510000-00007.

    Article  CAS  PubMed  Google Scholar 

  70. Gando S, Kameue T, Matsuda N, Hayakawa M, Ishitani T, Morimoto Y, Kemmotsu O. Combined activation of coagulation and inflammation has an important role in multiple organ dysfunction and poor outcome after severe trauma. Thromb Haemost. 2002;88:943–9.

    Article  CAS  PubMed  Google Scholar 

  71. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407:258–64. https://doi.org/10.1038/35025229.

    Article  CAS  PubMed  Google Scholar 

  72. Riewald M, Ruf W. Orchestration of coagulation protease signaling by tissue factor. Trends Cardiovasc Med. 2002;12:149–54. https://doi.org/10.1016/s1050-1738(02)00153-6.

    Article  CAS  PubMed  Google Scholar 

  73. Pawlinski R, Mackman N. Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis. Crit Care Med. 2004;32:S293–7. https://doi.org/10.1097/01.ccm.0000128445.95144.b8.

    Article  CAS  PubMed  Google Scholar 

  74. Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med. 2010;38:S35–42. https://doi.org/10.1097/CCM.0b013e3181c9e31d.

    Article  PubMed  Google Scholar 

  75. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5. https://doi.org/10.1126/science.1092385.

    Article  CAS  PubMed  Google Scholar 

  76. Xu J, Zhang X, Pelayo R, Monestier M, Ammollo CT, Semeraro F, Taylor FB, Esmon NL, Lupu F, Esmon CT. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009;15:1318–21. https://doi.org/10.1038/nm.2053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ito T. PAMPs and DAMPs as triggers for DIC. J Intensive Care. 2014;2:67. https://doi.org/10.1186/s40560-014-0065-0.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Alhamdi Y, Toh CH. Recent advances in pathophysiology of disseminated intravascular coagulation: the role of circulating histones and neutrophil extracellular traps. F1000Res. 2017;6:2143. https://doi.org/10.12688/f1000research.12498.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104–7. https://doi.org/10.1038/nature08780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gu X, Yao Y, Wu G, Lv T, Luo L, Song Y. The plasma mitochondrial DNA is an independent predictor for post-traumatic systemic inflammatory response syndrome. PLoS One. 2013;8:e72834. https://doi.org/10.1371/journal.pone.0072834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Xu J, Zhang X, Monestier M, Esmon NL, Esmon CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol. 2011;187:2626–31. https://doi.org/10.4049/jimmunol.1003930.

    Article  CAS  PubMed  Google Scholar 

  82. Allam R, Darisipudi MN, Tschopp J, Anders HJ. Histones trigger sterile inflammation by activating the NLRP3 inflammasome. Eur J Immunol. 2013;43:3336–42. https://doi.org/10.1002/eji.201243224.

    Article  CAS  PubMed  Google Scholar 

  83. Hu Z, Murakami T, Tamura H, Reich J, Kuwahara-Arai K, Iba T, Tabe Y, Nagaoka I. Neutrophil extracellular traps induce IL-1β production by macrophages in combination with lipopolysaccharide. Int J Mol Med. 2017;39:549–58. https://doi.org/10.3892/ijmm.2017.2870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Nakahara M, Ito T, Kawahara K, Yamamoto M, Nagasato T, Shrestha B, Yamada S, Miyauchi T, Higuchi K, Takenaka T, Yasuda T, Matsunaga A, Kakihana Y, Hashiguchi T, Kanmura Y, Maruyama I. Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism. PLoS One. 2013;8:e75961. https://doi.org/10.1371/journal.pone.0075961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Carestia A, Rivadeneyra L, Romaniuk MA, Fondevila C, Negrotto S, Schattner M. Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Thromb Haemost. 2013;110:1035–45. https://doi.org/10.1160/th13-02-0174.

    Article  CAS  PubMed  Google Scholar 

  86. Fuchs TA, Bhandari AA, Wagner DD. Histones induce rapid and profound thrombocytopenia in mice. Blood. 2011;118:3708–14. https://doi.org/10.1182/blood-2011-01-332676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Alhamdi Y, Abrams ST, Lane S, Wang G, Toh CH. Histone-associated thrombocytopenia in patients who are critically ill. JAMA. 2016;315:817–9. https://doi.org/10.1001/jama.2016.0136.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Semeraro F, Ammollo CT, Morrissey JH, Dale GL, Friese P, Esmon NL, Esmon CT. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood. 2011;118:1952–61. https://doi.org/10.1182/blood-2011-03-343061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. McDonald B, Davis RP, Kim SJ, Tse M, Esmon CT, Kolaczkowska E, Jenne CN. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood. 2017;129:1357–67. https://doi.org/10.1182/blood-2016-09-741298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Østerud B, Bjørklid E. The tissue factor pathway in disseminated intravascular coagulation. Semin Thromb Hemost. 2001;27:605–17. https://doi.org/10.1055/s-2001-18866.

    Article  PubMed  Google Scholar 

  91. Shimura M, Wada H, Wakita Y, Nakase T, Hiyoyama K, Nagaya S, Mori Y, Shiku H. Plasma tissue factor and tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation. Am J Hematol. 1997;55:169–74. https://doi.org/10.1002/(sici)1096-8652(199707)55:4<169::aid-ajh1>3.0.co;2-q.

    Article  CAS  PubMed  Google Scholar 

  92. Yang X, Li L, Liu J, Lv B, Chen F. Extracellular histones induce tissue factor expression in vascular endothelial cells via TLR and activation of NF-κB and AP-1. Thromb Res. 2016;137:211–8. https://doi.org/10.1016/j.thromres.2015.10.012.

    Article  CAS  PubMed  Google Scholar 

  93. Kim JE, Yoo HJ, Gu JY, Kim HK. Histones induce the procoagulant phenotype of endothelial cells through tissue factor up-regulation and thrombomodulin down-regulation. PLoS One. 2016;11:e0156763. https://doi.org/10.1371/journal.pone.0156763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Barranco-Medina S, Pozzi N, Vogt AD, Di Cera E. Histone H4 promotes prothrombin autoactivation. J Biol Chem. 2013;288:35749–57. https://doi.org/10.1074/jbc.M113.509786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Semeraro F, Ammollo CT, Esmon NL, Esmon CT. Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells. J Thromb Haemost. 2014;12:1697–702. https://doi.org/10.1111/jth.12677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107:15880–5. https://doi.org/10.1073/pnas.1005743107.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P, Song Y, Tzima E, Kennerknecht E, Niepmann M, von Bruehl ML, Sedding D, Massberg S, Günther A, Engelmann B, Preissner KT. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A. 2007;104:6388–93. https://doi.org/10.1073/pnas.0608647104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Oehmcke S, Mörgelin M, Herwald H. Activation of the human contact system on neutrophil extracellular traps. J Innate Immun. 2009;1:225–30. https://doi.org/10.1159/000203700.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Park HS, Gu J, You HJ, Kim JE, Kim HK. Factor XII-mediated contact activation related to poor prognosis in disseminated intravascular coagulation. Thromb Res. 2016;138:103–7. https://doi.org/10.1016/j.thromres.2015.12.011.

    Article  CAS  PubMed  Google Scholar 

  100. Ammollo CT, Semeraro F, Xu J, Esmon NL, Esmon CT. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost. 2011;9:1795–803. https://doi.org/10.1111/j.1538-7836.2011.04422.x.

    Article  CAS  PubMed  Google Scholar 

  101. Sun S, Sursal T, Adibnia Y, Zhao C, Zheng Y, Li H, Otterbein LE, Hauser CJ, Itagaki K. Mitochondrial DAMPs increase endothelial permeability through neutrophil dependent and independent pathways. PLoS One. 2013;8:e59989. https://doi.org/10.1371/journal.pone.0059989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Asakura H, Ontachi Y, Mizutani T, Kato M, Ito T, Saito M, Morishita E, Yamazaki M, Aoshima K, Takami A, Yoshida T, Suga Y, Miyamoto K, Nakao S. Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation. Eur J Haematol. 2001;67:170–5. https://doi.org/10.1034/j.1600-0609.2001.5790508.x.

    Article  CAS  PubMed  Google Scholar 

  103. Komissarov AA, Florova G, Idell S. Effects of extracellular DNA on plasminogen activation and fibrinolysis. J Biol Chem. 2011;286:41949–62. https://doi.org/10.1074/jbc.M111.301218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gould TJ, Vu TT, Stafford AR, Dwivedi DJ, Kim PY, Fox-Robichaud AE, Weitz JI, Liaw PC. Cell-free DNA modulates clot structure and impairs fibrinolysis in sepsis. Arterioscler Thromb Vasc Biol. 2015;35:2544–53. https://doi.org/10.1161/atvbaha.115.306035.

    Article  CAS  PubMed  Google Scholar 

  105. Longstaff C, Varjú I, Sótonyi P, Szabó L, Krumrey M, Hoell A, Bóta A, Varga Z, Komorowicz E, Kolev K. Mechanical stability and fibrinolytic resistance of clots containing fibrin, DNA, and histones. J Biol Chem. 2013;288:6946–56. https://doi.org/10.1074/jbc.M112.404301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Varjú I, Longstaff C, Szabó L, Farkas ÁZ, Varga-Szabó VJ, Tanka-Salamon A, Machovich R, Kolev K. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Haemost. 2015;113:1289–98. https://doi.org/10.1160/th14-08-0669.

    Article  PubMed  Google Scholar 

  107. Hoffman M, Monroe DM III. A cell-based model of hemostasis. Thromb Haemost. 2001;85:958–65.

    Article  CAS  PubMed  Google Scholar 

  108. Bajzar L, Morser J, Nesheim M. TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem. 1996;271:16603–8. https://doi.org/10.1074/jbc.271.28.16603.

    Article  CAS  PubMed  Google Scholar 

  109. Rezaie AR. Regulation of the protein C anticoagulant and antiinflammatory pathways. Curr Med Chem. 2010;17:2059–69. https://doi.org/10.2174/092986710791233706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Campbell WD, Lazoura E, Okada N, Okada H. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Microbiol Immunol. 2002;46:131–4. https://doi.org/10.1111/j.1348-0421.2002.tb02669.x.

    Article  CAS  PubMed  Google Scholar 

  111. Leung LL, Myles T, Nishimura T, Song JJ, Robinson WH. Regulation of tissue inflammation by thrombin-activatable carboxypeptidase B (or TAFI). Mol Immunol. 2008;45:4080–3. https://doi.org/10.1016/j.molimm.2008.07.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bajzar L, Jain N, Wang P, Walker JB. Thrombin activatable fibrinolysis inhibitor: not just an inhibitor of fibrinolysis. Crit Care Med. 2004;32:S320–4. https://doi.org/10.1097/01.ccm.0000126361.00450.b1.

    Article  CAS  PubMed  Google Scholar 

  113. Levin EG, Marzec U, Anderson J, Harker LA. Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells. J Clin Invest. 1984;74:1988–95. https://doi.org/10.1172/jci111620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gelehrter TD, Sznycer-Laszuk R. Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells. J Clin Invest. 1986;77:165–9. https://doi.org/10.1172/jci112271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang W, Boffa MB, Bajzar L, Walker JB, Nesheim ME. A study of the mechanism of inhibition of fibrinolysis by activated thrombin-activable fibrinolysis inhibitor. J Biol Chem. 1998;273:27176–81. https://doi.org/10.1074/jbc.273.42.27176.

    Article  CAS  PubMed  Google Scholar 

  116. Bouma BN, Meijers JC. Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U). J Thromb Haemost. 2003;1:1566–74. https://doi.org/10.1046/j.1538-7836.2003.00329.x.

    Article  CAS  PubMed  Google Scholar 

  117. Yanagida Y, Gando S, Sawamura A, Hayakawa M, Uegaki S, Kubota N, Homma T, Ono Y, Honma Y, Wada T, Jesmin S. Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock. Surgery. 2013;154:48–57. https://doi.org/10.1016/j.surg.2013.02.004.

    Article  PubMed  Google Scholar 

  118. Dunbar NM, Chandler WL. Thrombin generation in trauma patients. Transfusion. 2009;49:2652–60. https://doi.org/10.1111/j.1537-2995.2009.02335.x.

    Article  CAS  PubMed  Google Scholar 

  119. Chandler WL. Procoagulant activity in trauma patients. Am J Clin Pathol. 2010;134:90–6. https://doi.org/10.1309/ajcp3wpoyskk6bfe.

    Article  PubMed  Google Scholar 

  120. Gando S, Nanzaki S, Sasaki S, Kemmotsu O. Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation. Thromb Haemost. 1998;79:1111–5.

    Article  CAS  PubMed  Google Scholar 

  121. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995;273:117–23.

    Article  CAS  PubMed  Google Scholar 

  122. Gando S, Nanzaki S, Kemmotsu O. Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis. Ann Surg. 1999;229:121–7. https://doi.org/10.1097/00000658-199901000-00016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wada T, Shiraishi A, Gando S. Disseminated intravascular coagulation (DIC) immediately after trauma predicts a poor prognosis of severely injured patients: a sub-analysis of a multicenter prospective study on disseminated intravascular coagulation in trauma. Intensive Care Med. 2021;11(1):11031.

    CAS  Google Scholar 

  124. Gando S. Hemostasis and thrombosis in trauma patients. Semin Thromb Hemost. 2015;41:26–34. https://doi.org/10.1055/s-0034-1398378.

    Article  CAS  PubMed  Google Scholar 

  125. Innes D, Sevitt S. Coagulation and fibrinolysis in injured patients. J Clin Pathol. 1964;17:1–13. https://doi.org/10.1136/jcp.17.1.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Eeles GH, Sevitt S. Microthrombosis in injured and burned patients. J Pathol Bacteriol. 1967;93:275–93. https://doi.org/10.1002/path.1700930126.

    Article  CAS  PubMed  Google Scholar 

  127. Hardaway RM. The significance of coagulative and thrombotic changes after haemorrhage and injury. J Clin Pathol Suppl (R Coll Pathol). 1970;4:110–20. https://doi.org/10.1136/jcp.s3-4.1.110.

    Article  CAS  Google Scholar 

  128. Nuytinck HK, Offermans XJ, Kubat K, Goris JA. Whole-body inflammation in trauma patients. An autopsy study. Arch Surg. 1988;123:1519–24. https://doi.org/10.1001/archsurg.1988.01400360089016.

    Article  CAS  PubMed  Google Scholar 

  129. Stein SC, Graham DI, Chen XH, Smith DH. Association between intravascular microthrombosis and cerebral ischemia in traumatic brain injury. Neurosurgery. 2004;54:687–91; discussion 91. https://doi.org/10.1227/01.neu.0000108641.98845.88.

    Article  PubMed  Google Scholar 

  130. Kaufman HH, Hui KS, Mattson JC, Borit A, Childs TL, Hoots WK, Bernstein DP, Makela ME, Wagner KA, Kahan BD, et al. Clinicopathological correlations of disseminated intravascular coagulation in patients with head injury. Neurosurgery. 1984;15:34–42. https://doi.org/10.1227/00006123-198407000-00008.

    Article  CAS  PubMed  Google Scholar 

  131. Gando S, Nanzaki S, Kemmotsu O. Coagulofibrinolytic changes after isolated head injury are not different from those in trauma patients without head injury. J Trauma. 1999;46:1070–6; discussion 6–7. https://doi.org/10.1097/00005373-199906000-00018.

    Article  CAS  PubMed  Google Scholar 

  132. Taylor FB Jr, Chang AC, Peer GT, Mather T, Blick K, Catlett R, Lockhart MS, Esmon CT. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood. 1991;78:364–8.

    Article  PubMed  Google Scholar 

  133. Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767–804. https://doi.org/10.1146/annurev.iy.11.040193.004003.

    Article  CAS  PubMed  Google Scholar 

  134. Aird WC. Endothelial cell dynamics and complexity theory. Crit Care Med. 2002;30:S180–5. https://doi.org/10.1097/00003246-200205001-00002.

    Article  CAS  PubMed  Google Scholar 

  135. Liaw PC, Ito T, Iba T, Thachil J, Zeerleder S. DAMP and DIC: the role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev. 2016;30:257–61. https://doi.org/10.1016/j.blre.2015.12.004.

    Article  CAS  PubMed  Google Scholar 

  136. Kim JE, Lee N, Gu JY, Yoo HJ, Kim HK. Circulating levels of DNA-histone complex and dsDNA are independent prognostic factors of disseminated intravascular coagulation. Thromb Res. 2015;135:1064–9. https://doi.org/10.1016/j.thromres.2015.03.014.

    Article  CAS  PubMed  Google Scholar 

  137. Delabranche X, Stiel L, Severac F, Galoisy AC, Mauvieux L, Zobairi F, Lavigne T, Toti F, Anglès-Cano E, Meziani F, Boisramé-Helms J. Evidence of netosis in septic shock-induced disseminated intravascular coagulation. Shock. 2017;47:313–7. https://doi.org/10.1097/shk.0000000000000719.

    Article  CAS  PubMed  Google Scholar 

  138. Abrams ST, Morton B, Alhamdi Y, Alsabani M, Lane S, Welters ID, Wang G, Toh CH. A novel assay for neutrophil extracellular trap formation independently predicts disseminated intravascular coagulation and mortality in critically ill patients. Am J Respir Crit Care Med. 2019;200:869–80. https://doi.org/10.1164/rccm.201811-2111OC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Alhamdi Y, Abrams ST, Cheng Z, Jing S, Su D, Liu Z, Lane S, Welters I, Wang G, Toh CH. Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med. 2015;43:2094–103. https://doi.org/10.1097/ccm.0000000000001162.

    Article  CAS  PubMed  Google Scholar 

  140. Alhamdi Y, Zi M, Abrams ST, Liu T, Su D, Welters I, Dutt T, Cartwright EJ, Wang G, Toh CH. Circulating histone concentrations differentially affect the predominance of left or right ventricular dysfunction in critical illness. Crit Care Med. 2016;44:e278–88. https://doi.org/10.1097/ccm.0000000000001413.

    Article  PubMed  Google Scholar 

  141. Cheng Z, Abrams ST, Alhamdi Y, Toh J, Yu W, Wang G, Toh CH. Circulating histones are major mediators of multiple organ dysfunction syndrome in acute critical illnesses. Crit Care Med. 2019;47:e677–e84. https://doi.org/10.1097/ccm.0000000000003839.

    Article  PubMed  Google Scholar 

  142. Russell RT, Christiaans SC, Nice TR, Banks M, Mortellaro VE, Morgan C, Duhachek-Stapelman A, Lisco SJ, Kerby JD, Wagener BM, Chen MK, Pittet JF. Histone-complexed DNA fragments levels are associated with coagulopathy, endothelial cell damage, and increased mortality after severe pediatric trauma. Shock. 2018;49:44–52. https://doi.org/10.1097/shk.0000000000000902.

    Article  CAS  PubMed  Google Scholar 

  143. Gamberucci A, Fulceri R, Marcolongo P, Pralong WF, Benedetti A. Histones and basic polypeptides activate Ca2+/cation influx in various cell types. Biochem J. 1998;331(Pt 2):623–30. https://doi.org/10.1042/bj3310623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Fattahi F, Grailer JJ, Jajou L, Zetoune FS, Andjelkovic AV, Ward PA. Organ distribution of histones after intravenous infusion of FITC histones or after sepsis. Immunol Res. 2015;61:177–86. https://doi.org/10.1007/s12026-015-8628-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709. https://doi.org/10.1056/nejm200103083441001.

    Article  CAS  PubMed  Google Scholar 

  146. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Pénzes I, Kübler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286:1869–78. https://doi.org/10.1001/jama.286.15.1869.

    Article  CAS  PubMed  Google Scholar 

  147. Fourrier F. Severe sepsis, coagulation, and fibrinolysis: dead end or one way? Crit Care Med. 2012;40:2704–8. https://doi.org/10.1097/CCM.0b013e318258ff30.

    Article  PubMed  Google Scholar 

  148. Dhainaut JF, Yan SB, Joyce DE, Pettilä V, Basson B, Brandt JT, Sundin DP, Levi M. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost. 2004;2:1924–33. https://doi.org/10.1111/j.1538-7836.2004.00955.x.

    Article  CAS  PubMed  Google Scholar 

  149. Kienast J, Juers M, Wiedermann CJ, Hoffmann JN, Ostermann H, Strauss R, Keinecke HO, Warren BL, Opal SM. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost. 2006;4:90–7. https://doi.org/10.1111/j.1538-7836.2005.01697.x.

    Article  CAS  PubMed  Google Scholar 

  150. Umemura Y, Yamakawa K, Ogura H, Yuhara H, Fujimi S. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials. J Thromb Haemost. 2016;14:518–30. https://doi.org/10.1111/jth.13230.

    Article  CAS  PubMed  Google Scholar 

  151. Murao S, Yamakawa K. A systematic summary of systematic reviews on anticoagulant therapy in sepsis. J Clin Med. 2019;8:1869. https://doi.org/10.3390/jcm8111869.

    Article  PubMed Central  Google Scholar 

  152. Ely EW, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, Vincent JL, Macias WL, Bernard GR. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med. 2003;31:12–9. https://doi.org/10.1097/00003246-200301000-00002.

    Article  CAS  PubMed  Google Scholar 

  153. Wiedermann CJ, Hoffmann JN, Juers M, Ostermann H, Kienast J, Briegel J, Strauss R, Keinecke HO, Warren BL, Opal SM. High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med. 2006;34:285–92. https://doi.org/10.1097/01.ccm.0000194731.08896.99.

    Article  CAS  PubMed  Google Scholar 

  154. Kalil AC, LaRosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis. 2012;12:678–86. https://doi.org/10.1016/s1473-3099(12)70157-3.

    Article  CAS  PubMed  Google Scholar 

  155. Yamakawa K, Aihara M, Ogura H, Yuhara H, Hamasaki T, Shimazu T. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis. J Thromb Haemost. 2015;13:508–19. https://doi.org/10.1111/jth.12841.

    Article  CAS  PubMed  Google Scholar 

  156. Yamakawa K, Gando S, Ogura H, Umemura Y, Kabata D, Shintani A, Shiraishi A, Saitoh D, Fujishima S, Mayumi T, Kushimoto S, Abe T, Shiino Y, Nakada TA, Tarui T, Hifumi T, Otomo Y, Okamoto K, Kotani J, Sakamoto Y, Sasaki J, Shiraishi SI, Takuma K, Tsuruta R, Hagiwara A, Masuno T, Takeyama N, Yamashita N, Ikeda H, Ueyama M, Fujimi S. Identifying sepsis populations benefitting from anticoagulant therapy: a prospective cohort study incorporating a restricted cubic spline regression model. Thromb Haemost. 2019;119:1740–51. https://doi.org/10.1055/s-0039-1693740.

    Article  PubMed  Google Scholar 

  157. Umemura Y, Yamakawa K. Optimal patient selection for anticoagulant therapy in sepsis: an evidence-based proposal from Japan. J Thromb Haemost. 2018;16:462–4. https://doi.org/10.1111/jth.13946.

    Article  CAS  PubMed  Google Scholar 

  158. Wiedermann CJ, Kaneider NC. Comparison of mechanisms after post-hoc analyses of the drotrecogin alfa (activated) and antithrombin III trials in severe sepsis. Ann Med. 2004;36:194–203. https://doi.org/10.1080/07853890410027943.

    Article  CAS  PubMed  Google Scholar 

  159. Wiedermann CJ. Anticoagulant therapy for septic coagulopathy and disseminated intravascular coagulation: where do KyberSept and SCARLET leave us? Acute Med Surg. 2020;7:e477. https://doi.org/10.1002/ams2.477.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Dhainaut JF, Shorr AF, Macias WL, Kollef MJ, Levi M, Reinhart K, Nelson DR. Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure. Crit Care Med. 2005;33:341–8. https://doi.org/10.1097/01.ccm.0000153520.31562.48.

    Article  CAS  PubMed  Google Scholar 

  161. Ogura H, Gando S, Saitoh D, Takeyama N, Kushimoto S, Fujishima S, Mayumi T, Araki T, Ikeda H, Kotani J, Miki Y, Shiraishi S, Suzuki K, Suzuki Y, Takuma K, Tsuruta R, Yamaguchi Y, Yamashita N, Aikawa N. Epidemiology of severe sepsis in Japanese intensive care units: a prospective multicenter study. J Infect Chemother. 2014;20:157–62. https://doi.org/10.1016/j.jiac.2013.07.006.

    Article  PubMed  Google Scholar 

  162. Gando S, Shiraishi A, Yamakawa K, Ogura H, Saitoh D, Fujishima S, Mayumi T, Kushimoto S, Abe T, Shiino Y, Nakada TA, Tarui T, Hifumi T, Otomo Y, Okamoto K, Umemura Y, Kotani J, Sakamoto Y, Sasaki J, Shiraishi SI, Takuma K, Tsuruta R, Hagiwara A, Masuno T, Takeyama N, Yamashita N, Ikeda H, Ueyama M, Fujimi S. Role of disseminated intravascular coagulation in severe sepsis. Thromb Res. 2019;178:182–8. https://doi.org/10.1016/j.thromres.2019.04.025.

    Article  CAS  PubMed  Google Scholar 

  163. Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK, Nielsen JD, Dempfle CE, Levi M, Toh CH. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013; https://doi.org/10.1111/jth.12155.

  164. Hayakawa M, Gando S, Ono Y, Wada T, Yanagida Y, Sawamura A. Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma: a retrospective observational study. Semin Thromb Hemost. 2015;41:35–42. https://doi.org/10.1055/s-0034-1398379.

    Article  CAS  PubMed  Google Scholar 

  165. Grundman C, Plesker R, Kusch M, Hanschmann KM, Eich S, Seitz R, König H. Prothrombin overload causes thromboembolic complications in prothrombin complex concentrates: in vitro and in vivo evidence. Thromb Haemost. 2005;94:1338–9.

    Article  PubMed  Google Scholar 

  166. Grottke O, Rossaint R, Henskens Y, van Oerle R, Ten Cate H, Spronk HM. Thrombin generation capacity of prothrombin complex concentrate in an in vitro dilutional model. PLoS One. 2013;8:e64100. https://doi.org/10.1371/journal.pone.0064100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Grottke O, Braunschweig T, Spronk HM, Esch S, Rieg AD, van Oerle R, ten Cate H, Fitzner C, Tolba R, Rossaint R. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood. 2011;118:1943–51. https://doi.org/10.1182/blood-2011-03-343046.

    Article  CAS  PubMed  Google Scholar 

  168. Schöchl H, Voelckel W, Maegele M, Kirchmair L, Schlimp CJ. Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Crit Care. 2014;18:R147. https://doi.org/10.1186/cc13982.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M. Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC)—a multicenter co-operative double-blind trial in comparison with heparin. Thromb Res. 1993;72:475–500. https://doi.org/10.1016/0049-3848(93)90109-2.

    Article  CAS  PubMed  Google Scholar 

  170. Angus DC. Drotrecogin alfa (activated)…a sad final fizzle to a roller-coaster party. Crit Care. 2012;16:107. https://doi.org/10.1186/cc11152.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Allingstrup M, Wetterslev J, Ravn FB, Møller AM, Afshari A. Antithrombin III for critically ill patients: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med. 2016;42:505–20. https://doi.org/10.1007/s00134-016-4225-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Iba T, Thachil J. Is antithrombin III for sepsis-associated disseminated intravascular coagulation really ineffective? Intensive Care Med. 2016;42:1193–4. https://doi.org/10.1007/s00134-016-4288-5.

    Article  PubMed  Google Scholar 

  173. Gando S, Saitoh D, Ishikura H, Ueyama M, Otomo Y, Oda S, Kushimoto S, Tanjoh K, Mayumi T, Ikeda T, Iba T, Eguchi Y, Okamoto K, Ogura H, Koseki K, Sakamoto Y, Takayama Y, Shirai K, Takasu O, Inoue Y, Mashiko K, Tsubota T, Endo S. A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis. Crit Care. 2013;17:R297. https://doi.org/10.1186/cc13163.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost. 2014;12:1470–9. https://doi.org/10.1111/jth.12643.

    Article  CAS  PubMed  Google Scholar 

  175. Tagami T, Matsui H, Fushimi K, Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis. Thromb Haemost. 2015;114:537–45. https://doi.org/10.1160/th15-01-0053.

    Article  PubMed  Google Scholar 

  176. Wiedermann CJ. Antithrombin concentrate use in disseminated intravascular coagulation of sepsis: meta-analyses revisited. J Thromb Haemost. 2018;16:455–7. https://doi.org/10.1111/jth.13950.

    Article  CAS  PubMed  Google Scholar 

  177. Tagami T. Antithrombin concentrate use in sepsis-associated disseminated intravascular coagulation: re-evaluation of a ‘pendulum effect’ drug using a nationwide database. J Thromb Haemost. 2018;16:458–61. https://doi.org/10.1111/jth.13948.

    Article  CAS  PubMed  Google Scholar 

  178. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, Hirayama A, Matsuda T, Asakura H, Nakashima M, Aoki N. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5:31–41. https://doi.org/10.1111/j.1538-7836.2006.02267.x.

    Article  CAS  PubMed  Google Scholar 

  179. Vincent JL, Ramesh MK, Ernest D, LaRosa SP, Pachl J, Aikawa N, Hoste E, Levy H, Hirman J, Levi M, Daga M, Kutsogiannis DJ, Crowther M, Bernard GR, Devriendt J, Puigserver JV, Blanzaco DU, Esmon CT, Parrillo JE, Guzzi L, Henderson SJ, Pothirat C, Mehta P, Fareed J, Talwar D, Tsuruta K, Gorelick KJ, Osawa Y, Kaul I. A randomized, double-blind, placebo-controlled, phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med. 2013;41:2069–79. https://doi.org/10.1097/CCM.0b013e31828e9b03.

    Article  CAS  PubMed  Google Scholar 

  180. Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY, Pettilä V, Wittebole X, Meziani F, Mercier E, Lobo SM, Barie PS, Crowther M, Esmon CT, Fareed J, Gando S, Gorelick KJ, Levi M, Mira JP, Opal SM, Parrillo J, Russell JA, Saito H, Tsuruta K, Sakai T, Fineberg D. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA. 2019;321:1993–2002. https://doi.org/10.1001/jama.2019.5358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. van der Poll T. Recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy: another negative sepsis trial? JAMA. 2019;321:1978–80. https://doi.org/10.1001/jama.2019.5792.

    Article  PubMed  Google Scholar 

  182. Levi M, Vincent JL, Tanaka K, Radford AH, Kayanoki T, Fineberg DA, Hoppensteadt D, Fareed J. Effect of a recombinant human soluble thrombomodulin on baseline coagulation biomarker levels and mortality outcome in patients with sepsis-associated coagulopathy. Crit Care Med. 2020;48:1140–7. https://doi.org/10.1097/ccm.0000000000004426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Yamakawa K, Murao S, Aihara M. Recombinant human soluble thrombomodulin in sepsis-induced coagulopathy: an updated systematic review and meta-analysis. Thromb Haemost. 2019;119:56–65. https://doi.org/10.1055/s-0038-1676345.

    Article  PubMed  Google Scholar 

  184. Yamakawa K, Levy JH, Iba T. Recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy (SCARLET): an updated meta-analysis. Crit Care. 2019;23:302. https://doi.org/10.1186/s13054-019-2587-2.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Valeriani E, Squizzato A, Gallo A, Porreca E, Vincent JL, Iba T, Hagiwara A, Di Nisio M. Efficacy and safety of recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy: a systematic review and meta-analysis. J Thromb Haemost. 2020;18:1618–25. https://doi.org/10.1111/jth.14812.

    Article  CAS  PubMed  Google Scholar 

  186. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejía-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32. https://doi.org/10.1016/s0140-6736(10)60835-5.

    Article  CAS  PubMed  Google Scholar 

  187. Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, Dewan Y, Gando S, Guyatt G, Hunt BJ, Morales C, Perel P, Prieto-Merino D, Woolley T. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377:1096–101, 101.e1–2. https://doi.org/10.1016/s0140-6736(11)60278-x.

    Article  CAS  PubMed  Google Scholar 

  188. CRASH-3 Trial Collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019;394:1713–23. https://doi.org/10.1016/s0140-6736(19)32233-0.

    Article  CAS  Google Scholar 

  189. Wildhagen KC, García de Frutos P, Reutelingsperger CP, Schrijver R, Aresté C, Ortega-Gómez A, Deckers NM, Hemker HC, Soehnlein O, Nicolaes GA. Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis. Blood. 2014;123:1098–101. https://doi.org/10.1182/blood-2013-07-514984.

    Article  CAS  PubMed  Google Scholar 

  190. Hogwood J, Pitchford S, Mulloy B, Page C, Gray E. Heparin and non-anticoagulant heparin attenuate histone-induced inflammatory responses in whole blood. PLoS One. 2020;15:e0233644. https://doi.org/10.1371/journal.pone.0233644.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood. 2014;123:2768–76. https://doi.org/10.1182/blood-2013-10-463646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Spero JA, Lewis JH, Hasiba U. Disseminated intravascular coagulation. Findings in 346 patients. Thromb Haemost. 1980;43:28–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Acute and Critical Center, Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan

    Satoshi Gando

  2. Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan

    Satoshi Gando & Takeshi Wada

Authors
  1. Satoshi Gando
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takeshi Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Trauma Surgery, University Hospital Zürich, Zürich, Switzerland

    Hans-Christoph Pape

  2. Department of Orthopaedic Surgery & Sports Medicine, The University of South Florida Morsani College of Medicine, Tampa, FL, USA

    Joseph Borrelli Jr.

  3. Ernest E. Moore Shock Trauma Center at Denver Health, University of Colorado, Denver, CO, USA

    Ernest E. Moore

  4. Klinik für Traumatologie, University Hospital of Zürich, Zürich, Switzerland

    Roman Pfeifer

  5. Rocky Vista University, College of Osteopathic Medicine, Parker, CO, USA

    Philip F. Stahel

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gando, S., Wada, T. (2022). ICU Management: Disseminated Intravascular Coagulation (DIC). In: Pape, HC., Borrelli Jr., J., Moore, E.E., Pfeifer, R., Stahel, P.F. (eds) Textbook of Polytrauma Management . Springer, Cham. https://doi.org/10.1007/978-3-030-95906-7_33

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-95906-7_33

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-95905-0

  • Online ISBN: 978-3-030-95906-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation